The overall goal of the Gynecologic Cancer Specialized Program of Research Excellence (SPORE) at MD Anderson Cancer Center is to conduct highly innovative translational research for the prevention and treatment of uterine cancers. Encompassed within this overall goal are the following goals of the program: 1) to develop novel therapeutic strategies for advanced and recurrent endometrial cancer, 2) to promote novel strategies for chemoprevention of endometrial cancer in high risk cohorts, including obese women, and 3) to incorporate molecular diagnostics into clinical decision-making. Over the last 5 years, as the only Uterine Cancer SPORE, we established a highly productive uterine cancer translational research community that is unparalleled in breadth and depth. This Proposal includes 4 Projects that display high translational impact and outstanding scientific merit, led by experienced translational scientists. Project 1, "Metformin for the Chemoprevention of Endometrial Cancer in Obese, Insulin-Resistant Women," includes a chemoprevention trial using metformin for obese, insulin-resistant women. Project 2, "Use of Endometrial Biomarkers for Prediction of Advanced Disease," seeks to determine if a panel of molecular biomarkers discovered during the first five years of the SPORE can address a specific and important clinical dilemma facing surgeons caring for women with endometrial cancer. Project 3, "EphA2 Targeting in Uterine Carcinoma," focuses on a novel therapeutic target, EphA2. EphA2 is overexpressed in a substantial proportion of uterine cancers, is associated with poor overall survival, and has been shown to regulate angiogenesis. This project will include a phase Ib clinical trial of an immunoconjugate that links an anti-cancer therapeutic to an antibody against EphA2. Project 4 "Targeting the PISK Signaling Pathway in Endometrial Carcinoma," focuses on the role of the phosphatidylinositol-3-kinase PI3K/PTEN/AKT/mT0R signaling pathway in endometrial tumorigenesis. Preliminary data suggests that mutations exist in multiple nodes of this pathway, and that responsiveness to pathway inhibitors may differ based on mutation. This project will include a phase II clinical trial assessing the efficacy of the PI3K inhibitor, GSK2126458A, in advanced endometrial carcinoma. Four Cores will support these projects. Core A (Administrative Core), Core B (Pathology Core), Core C Biomarkers Core, and Core D (Biostatistics and Bioinformatics Core).